Insulin-like growth factor-1 and post-ischemic brain injury

Guan, Jian; Bennet, Laura; Gluckman, Peter D.; Gunn, Alistair J.

doi:10.1016/j.pneurobio.2003.08.002

Cited by 195 publications

(163 citation statements)

References 181 publications

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“…These data seem to be in contradiction with data in the literature, inasmuch as an early increase in P-Akt has been described after in vitro exposure of neuronal cells to hypoxia (25) in an adult murine stroke model (26). These increases in P-Akt have been implicated in down-regulation of apoptosis through inhibition of pro-apoptotic mediators such as Bad, FasLigand, and caspases-9 and -3 as well as cytochrome-c release, indicating that increases in P-Akt after hypoxic-ischemic events may be protective (27,28). In our model of neonatal cerebral HI in P12 rats, we observed, however, a biphasic decline in P-Akt rather than an increase, suggesting that the change in P-Akt in neonatal animals will not contribute to neuroprotection.…”

Section: Discussionmentioning

confidence: 97%

Bilateral Molecular Changes in a Neonatal Rat Model of Unilateral Hypoxic-Ischemic Brain Damage

et al. 2006

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Perinatal hypoxia ischemia (HI) is a frequent cause of neonatal brain injury. This study aimed at describing molecular changes during the first 48 h after exposure of the neonatal rat brain to HI. Twelve-day-old rats were subjected to unilateral carotid artery occlusion and 90 min of 8% O 2 , leading to neuronal damage in the ipsilateral hemisphere only. Phosphorylated-Akt levels were decreased from 0.5 to 6 h post-HI, whereas the level of phosphorylated extracellular signal-related kinases (ERK)1/2 increased during this time frame. Hypoxia-inducible factor (HIF)-1␣ protein increased with a peak at 3 h after HI. mRNA expression for IL-␤ and tumor necrosis factor-␣ and -␤ started to increase at 6 h with a peak at 24 h post-HI. Expression of heat shock protein 70 was increased from 12 h after HI onwards in the ipsilateral hemisphere only. Surprisingly, HI changed the expression of cytokines, HIF1-␣ ,and P-Akt to the same extent in both the ipsi-as well as the contralateral hemisphere, although neuronal damage was unilateral. Exposure of animals to hypoxia without carotid artery occlusion induced similar changes in cytokines, HIF-1␣, and P-Akt. We conclude that during HI, hypoxia is sufficient to regulate multiple molecular mediators that may contribute, but are not sufficient, to induce long-term neuronal damage. A commonly used neonatal rat model to investigate hypoxic-ischemic brain damage is the Vannucci-Rice model. This model implicates unilateral common carotid artery ligation followed by inhalation of 8% O 2 for 1-2 h. This procedure leads to cerebral damage restricted to the hemisphere ipsilateral to the occluded artery (4).Early after induction of cerebral damage, death, and survival, kinase signalling pathways are known to be activated, including the phosphatidyl-inositol 3 kinase/Akt (PI3-K/Akt) and the ERK1/2 pathways. The phosphorylated forms of these kinases have been shown to be up-regulated after HI in vivo as well as in vitro and are thought to be involved in neuronal cell apoptosis (5-7). Activation of the PI3-K/Akt and the ERK1/2 signaling routes enhance translation of the transcription factor HIF-1␣ (8 -10). In addition, reduced cellular oxygen levels increase the stability of HIF-1␣ protein. More than 40 genes containing the promoter sequence for HIF-1␣ have been identified. Most of these genes play a key role in neuroprotective processes such as angiogenesis/vascular remodeling, erythropoiesis, glucose transport, glycolysis, iron transport, and cell proliferation/neuronal survival (11). Increased HIF-1␣ levels therefore regulate adaptation of the cell to a hypoxic environment (12). Another factor induced after HI that has been implicated in both cellular protection and damage, is HSP70. HSP70 is a chaperone molecule, which is induced in cells after stress such as heat, stretch, or hypoxia (13,14). Intracellular HSP70 is thought to protect cells by binding to denatured proteins, thereby preventing further denaturation or degradation of the proteins. In addition, there is evidence that...

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Section: Discussionmentioning

confidence: 97%

Bilateral Molecular Changes in a Neonatal Rat Model of Unilateral Hypoxic-Ischemic Brain Damage

et al. 2006

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“…However, it becomes a very potent neuroprotective compound when administered shortly after stroke induction. 12 IGF-I suppresses apoptosis through mechanisms involving activation of multiple protein kinase pathways, which are most likely to be important early in the latent phase of evolving programmed cell death. 12 This may explain why we found no difference in baseline stroke severity between patients with high and low IGF-I serum levels.…”

Section: Discussionmentioning

confidence: 99%

Insulin-Like Growth Factor I Serum Levels Influence Ischemic Stroke Outcome

Smedt

Brouns

Uyttenboogaart

et al. 2011

Stroke

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Background and Purpose— Insulin-like growth factor I (IGF-I) is neuroprotective in animal models of stroke. We investigated whether serum IGF-I levels in patients with acute ischemic stroke influence stroke severity and outcome. Methods— Concentrations of IGF-I and IGF binding protein 3 were measured in serum samples obtained within 6 hours after stroke onset from 255 patients who took part in the placebo arm of the United States and Canadian Lubeluzole in Acute Ischemic Stroke Study. Stroke severity was assessed with the National Institutes of Health Stroke Scale. Multivariate analysis was performed to assess the overall shift in modified Rankin Scale score and changes in the National Institutes of Health Stroke Scale score at 3 months. Survival curves were plotted using the Kaplan-Meier method, and the Cox proportional hazard model was used for multivariate analysis to investigate factors influencing survival. Results— After controlling for statistically relevant risk factors, subjects with high IGF-I levels or IGF-I/IGF binding protein 3 ratios had a better neurological and functional outcome at 3 months. Baseline stroke severity was not different between high and low IGF-I groups. In contrast to the low IGF-I group, neurological symptoms gradually improved from Day 3 in the high IGF-I group. Conclusions— Our results suggest that high serum IGF-I levels just after ischemic stroke onset are associated with neurological recovery and a better functional outcome.

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“…The observed increase in relative IGF-1 expression in the present study may account for the increase in cardiomyocyte size in the EtOH-exposed hearts and may be a compensatory response of the myocardium to the increased apoptosis. Indeed, compensatory upregulation of IGF-1 gene expression has been described in other tissues undergoing apoptosis (9,17). It is also possible that ethanol exposure results in altered relative IGF-1 gene expression via a direct effect on transcription of the gene or the rate at which the transcript is degraded.…”

Section: Discussionmentioning

confidence: 99%

Alcohol exposure during late gestation adversely affects myocardial development with implications for postnatal cardiac function

Goh

Bensley

Kenna

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Harding R, Black MJ. Alcohol exposure during late gestation adversely affects myocardial development with implications for postnatal cardiac function. Am J Physiol Heart Circ Physiol 300: H645-H651, 2011. First published November 12, 2010 doi:10.1152/ajpheart.00689.2010.-Prenatal exposure to high levels of ethanol is associated with cardiac malformations, but the effects of lower levels of exposure on the heart are unclear. Our aim was to investigate the effects of daily exposure to ethanol during late gestation, when cardiomyocytes are undergoing maturation, on the developing myocardium. Pregnant ewes were infused with either ethanol (0.75 g/kg) or saline for 1 h each day from gestational days 95 to 133 (term ϳ145 days); tissues were collected at 134 days. In sheep, cardiomyocytes mature during late gestation as in humans. Within the left ventricle (LV), cardiomyocyte number was determined using unbiased stereology and cardiomyocyte size and nuclearity determined using confocal microscopy. Collagen deposition was quantified using image analysis. Genes relating to cardiomyocyte proliferation and apoptosis were examined using quantitative real-time PCR. Fetal plasma ethanol concentration reached 0.11 g/dL after EtOH infusions. Ethanol exposure induced significant increases in relative heart weight, relative LV wall volume, and cardiomyocyte cross-sectional area. Ethanol exposure advanced LV maturation in that the proportion of binucleated cardiomyocytes increased by 12%, and the number of mononucleated cardiomyocytes was decreased by a similar amount. Apoptotic gene expression increased in the ethanol-exposed hearts, although there were no significant differences between groups in total cardiomyocyte number or interstitial collagen. Daily exposure to a moderate dose of ethanol in late gestation accelerates the maturation of cardiomyocytes and increases cardiomyocyte and LV tissue volume in the fetal heart. These effects on cardiomyocyte growth may program for long-term cardiac vulnerability.

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Insulin-like growth factor-1 and post-ischemic brain injury

Cited by 195 publications

References 181 publications

Bilateral Molecular Changes in a Neonatal Rat Model of Unilateral Hypoxic-Ischemic Brain Damage

Bilateral Molecular Changes in a Neonatal Rat Model of Unilateral Hypoxic-Ischemic Brain Damage

Insulin-Like Growth Factor I Serum Levels Influence Ischemic Stroke Outcome

Alcohol exposure during late gestation adversely affects myocardial development with implications for postnatal cardiac function

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